Pyrimidine derivatives and peocesb



n tural 5, less .umrao [STATE s. Par-Eur orrlca rrnmmnvannarva'rrvasannraocss orraaraamornasaus HansAndersagandKnrtWestphaLWaasignorato Elberfeld,

Germany, Win Chemical Company, Ina, New. York, N. 2., a corporation ofNew York No Drawing. Application December so, use, a. I

Germany rill No. 118,261. 1938 Jan s-1'1 28.

SClahna. (Cl-M) This invention relates to certain pyrimidine derlvativesand to processes of prep i s the same.

It is the, object of this invention toproduce j pyrimidine derivativeswhich in accordance with investigators pyrimidine derivatives oi thegeneral formula:

m-' -a\-x I a n -n n r l are required for the production of compounds ofa chemical constitution like or similar to the chemical structure ofvitamin B1 and related substances. In this formula R stands for alkyl,aryl or aralkyl groups, R) stands for an aliphatic radical, R and Rstand for hydrogen or alkyl and X stands for a reactive group such ashalogen, hydroxyl, -CO -R and -O--SO:R, B being an organic radical.After having succeeded in the manufacture of such formerly unknownpyrimidine derivatives, we indeed were able to prepare vitamin B1 andrelated substances from the said pyrimidine derivatives by chemicalsynthesis, the vitamin 31 itself being obtained by startingwithpyrimidines of the formula:

, N -CH HsC- -(IHr-X N; --NH| wherein X has the same meaning asindicated above.

In accordance with the present invention the pyrimidine derivativesabove specified are obtainable by reacting upon compounds of the formulafit-Y zt with an amidine of an alkyl, aryl or aralkyl carboxylic acid.In "the said formula R stands for an aliphatic radical, preferably foran alkylene group, for instance, for the methylene, ethylene, propyleneand beta-hydroxypropylene group, Z and Z which are attached to the samecarbon and etherifled, hy'droxymethyiene groups,'furthermore forcarbonyl groups the carbon atom oi which is substituted by hydrogen(formyl group) alkosy, aryloxy and aralkoxy groups (carboxylic estergroups), halogen atoms or amino groups (carboxylic acid halide and'amidc groups). and

it stands-for a reactive group asdenned above for X or for a group whichis convertible into voneoftheg'roupsstandingitorx;suchgroupsare,

for instance, carboaylic acid ester groups which are reduced tolrvdroxyl groups or are-converted into corresponding acid amide orhydroxide groups. The latter groups which themselves may aisostand for Yaretransformed into amino groupsaccordingtofloifmannsreactiomcurtius'reaction respectively. An acid-amide group may also be dehydraud to formthe crane group: the cyano group mayitseli stand for if: it is reducedto the HsN-CHs-gliiil alkoxy, aralkox'y and aryloxy groups may stand forY. They are split ofl'by hydrohalic acids to yield halogen groups.

Depending'on the kind, oi group representing Z and Z pyrimidines areobtained containing in the 4- and G-positions hydrogen atoms, hydrox ylor amino groups. Hydrogen atoms result from the reaction of thehydroxymethelene or etherifled lrvdrommethyle'ne group, hydroxyl groupsfrom the reaction of carboxylic acid ester, -halide and -gm1de g101lpsand amino groups from the reaction of cyano groups. Hydroxyl groups aresubsequently transformed as desired into hydrogen or into the aminogroup, preferably by first replacing them by halogen, for instance, bymeans of a phosphorus halide, preferably phosphorus oxyhalide and thenreplacing the'halogen atom I by hydrogen or an amino group under theaction of hydrogen or ammonia, a primary ,or a secondary amine.. Ifboth,gthe 4- and 6-positions are substituted by amino groups one of themis subsequently replaced by drogen by means of careful treatment withnitrous acid and alcohol. The reactions mentioned before may bedescribed in more detail as follows;

Amidines of organic carboxylic acids are condensed, for instance. withcompounds of the formula wherein It stands for an alkylene group, Zstands atom. of R stand for cyano, hydroxymethylene for a carboxylicacid ester group, Z stands for n Anacidamidgroup"gomayalsodirectlybereducedtotheHaNCHsgroup. Also etherifled hydroxylgroups that is .ai'ormyl grouper I with a still further-lecture, of I ja m g th'gflflgdhydrox'y methylene. theipresent inventiontlie b-halo'genalkyi com- 7 and'Y'sta'nds'for one oi-the groups above specified. 1pounds. are also obtainable from the l-amino-li- "Compounds oi thes'aidrformula'are acetlcaeid;

g round-"that when reacting upon the said com-'poundswithnitrousacidonlytheaminogroup'in 99-0 3 2" the-liaminoalkyl-radical is attacked. It is 110i!vv W- therefore possible whenstarting with i-amlno- (n stshoihs for awhole The s meon .sainosmyi-pyrimioines or their salts to obdensation is preferably'carried;out in the pres- .10, tain readily the 4-amino-5-hydroxyalkyl-pyc of o vn o 'g -e at r rimioihes'shdthe esters or the said hydroxr or elevated.temprature;. generally condensing. 7 com o It is possible to ohm themarshy meats 'bm e t e fltion the 4-amino-5-hydroxyalliyis for instance.the alcoholatea carbonaies and hy-. j pyrimidine compounds first formed,forinstance,

'droxides ot' 'metals andflllkecompounds- The -5 by the action 01'acids, acid anhydrides oral'go v by means of a halide oi phosphorus andreplacing. a m

e c r -m l 8180138 mpl yed in acid halides. Hydrohalic acid esters arein paraminoalbl-pyrimidinecompounds. .--We have the form of their metalcompounds. 2-Alky 1 ticular alsoobtained by the action of the halides(aryl, 'aralkyll-i-hydrokypyrihfldlnes S b of phophorus and of halidesof sulphurous acids,

m s e m ent ----(CH)Y for instance thionyl chloride. Furthermore the areprimarily obtained inthis condensation: The esters may also be obtaineddirectly from the.

' most convenient way to convert the i-ehydfox'y 4, amino 5aminoalkyl-pyrimidine compounds group into the amino group is' ySubstituting e I by reacting with nitrite in the presence 0: esh dronigroup by a halogen .atom, for instance, cess 00w}? acid. particularlyhydrohalic' the halogen atom by' a'substituted or non-sub- -'Ihe.a vedesc bed behaviour 01! the 4-amino'- sti uted amino group by tre m ntwith amm n s-aminoslkyi-pyrinuaihes to nitrite is surprising. r apr'mary-or secondary amine. For, since in 4-amino-5-alkyl-pyrimidinesthe When reacting for instance upon acetamidine amino group is exchangedfor the hy'droxyi with an alph -hydr m thylene-succinlc acid,-' group bythe action of nitrous acid (compare dialkylester. the reaction proceedsin accordanc Meyer-Jacobson Lehrbuch der organlschen th th followingreaction scheme: Chemie" vol. II, 3rd part, page 1179. paragraph NHri'o-cH Y f v si -t win-coon arc- A-cm-coonm' moi -cm-cooa E.

is. 1.0- 1 N. l...

H v o i I 3 g Y v B c- O -CHI-NHI u-on N-CH lIOB/ -Nm mcd-cns-com'h rhc--cm-corrn,

. n -Nm -Nm n, n-cn mc- -CH1CH:NH:

2z= -NH:

The reaction may also be carrledout 17711 1 18 1) it was to be expectedthat in thiscase also the cyano-scetic esters" which contain acarboxyllc amino groupstanding in 4-position would react acid ester srun. h compounds having with the nitrite. On the other hand, becauseformula of the known reactions of nitrous. acid with so compounds whichcontain an amino and an Nc-cn-(0m)-Y a'minoallryl grou in a groupingsimilar to that con oi 4-amino-5-aminoalkyl-pyrimidines, it was to h cuethe pyrimidine derivatives primarily be expected that by the action ofnitrite upon formed contain m the awosmon a hydroxyl4-amino-5-aminoallwl-pyrimidines 1,2,3-triazine group which subsequentlyis replaced by hydm compounds would be obtained (loc. cit. page 1509dine and t gga f g fz gg fwaf sf heme v The invention is iurtherillustrated by the folrepresented by the carboxylic acid ester group).lowing examples.' but is mt limited t first a i-smino-c-hydroipyrimidine derivative I Example 1 is obtained the G-hydroxyl group ofwhich is.sub- I 'sequently converted into hydrogen. The reac- 128 g.oi'acetamidlne hydrochloride and 269 g. tions proceed in the followingmanner: of iormyl-succinic acid ester are taken up in 200 NH ao-c=oN-c-on- .N'c-ci' roe n-cnecooa. rho-i a-caecooa -'s' inc- -cm-cooa --e Va NHe den N-OH N-CH N-CH 8.0-8 d-onecooa inc- Lemem Ei inc-t l-oneomar Jm m!- g I mtheatorementioned reactionaii-halogen alcos. of anhydrous.alcohol and boiled with a sob 'is obtained. The fi-halogen alkyllutionoi 32 g. of sodium in 500 cos. of anhydrous interest as initialmaterials for the synthesis of -am.in pyrid dines are of parti cularpractical alcohol for six hours. The hot solution is filtered 4 ooi!from the separated sodium chloride. On coolv'itaminm; 1: ins. colourlessneedles 0! the :i-methyi-i-h amass- I 3 oi the phosphorus oxychloride isthen distilled oil '5- under reduced pressure, and the residue decomposed by means of ice water. The acid solution is rendered alkaline withammonia and shaken with ether several times. The ethereal solution isdried and evaporated. The residue boils at 110 C. under 4 mm. pressure.The distillate solidifies to a crystalline magma and melts at 40-41 C.It is the 2-methyl 4-chloropyrimidyl- 5-acetic ester.

45 g. of this compouhd are heated for ten hours with 380 ccs. ofmethylalcoholic am- 1 monia in an autoclave to 120-130 C. After 111-lowing to cool, the separated crystals are filtered with suction andrecrystallized from aqueous alcohol. The2-methyl-4-amino-pyrimidyl-S-acego tic acid amide obtained formscolourless needles which melt at 250 C. 16.6 g. of this compound aredissolved in 'a solution of 16 g. or bromine in 200 cos. of2.5-normal-potassium hydroxide solution.

shaken with ether, the ethereal solution dried and freed from the ether.Theresidue sublimes in vacuo in firm rhomba which melt at 132 C.

The crystals are the 2-methyl-4-amino-5-amin0- methyl-pyrimidine. Thepicrate melts at 224- 225 C.; the hydrochloride melts at 268 C. withdecomposition. v r

The same compoundcan also be obtained from theZ-methyl-4-hydrcxypyrimidyl-5-acetic acid ethyl ester by way of the5-.acetic acid hydrazide by converting the hydrazide according to theCurtius reaction into the 5-aminomethyl compound and thenconverting thehydroxyl group inthe 4-position into an amino group in the man- 40 nerindicated above.

when using instead oi'acetamidine hydrochloride the equivalent quantityotproploamidine hydrochloride and working otherwise as described above,first the 2-ethyl-4-hydroxypyrimidyl-5- acetic ester melting" at 164 0.is obtained. It is converted into the 2-ethyl-4-chloropyrimidyl-5-acetic ester boiling under 2 mm. pressure at 126- 127 C. and the latterinto the 2-ethyl-j4-aminopyrlmidyl-5-acetamide melting at 236 C. thelatter the hydrochloride of the 2-ethyl-4-amino-5-amlnomethyl-pyrimidine is obtained in colorless crystals meltingat 248-25() C. with decomposition.

The 5-aminoalkyl compounds may be transiormed'into 5-halogenalkylcompounds in the foliollowin'g manner:

. 63.4 g. of 2-methyl-4amino-S-aminomethylpyrimidine-hydrochloride aredissolved in 600 cos.

of water at 50-60 C. At this temperature a soludo tion 0122 g. of sodiumnitrite in 200 ccs. of water is added drop by drop. The mixture isheated i'or zhours to 50-60 C., 45 g. of anhydrous sodium carbonate areadded and the mixture is evaporated to dryness under reduced pressure.

C. 20 g. of the said compound are dissolved in 300 cos. of glacialacetic acid and/hydrobromic 'acid "is introduced into the solution.Thereby the temperature rises to 60 C. The hydrobromide oi the alcoholfirst precipitated dissolves and the hydrobromide oi the 2-methyl-4-amino-5-bromo- 50 ccs; oi 50% potassium hydroxide'solu- 25 tionare added. After cooling, the solution is From 50 methyl-pyrimidineseparates gradually in thin crystals. The crystals are filtered withsuctionand washed with glacial acetic acid and ether.

They melt at 208 C. with decomposition.

From the above mentioned E-hydroxymethyl compound the benaenesulphonicacid ester is obtained as i'ollows: v

13.9 g. of 2- -methyl-4-amino-5-hydroxymethylpyrimidine are ilnelypowdered and heated with 20 g. of benzene sulphochloride during 1 hourto C. The reaction product is treated with ether. The yellowish coloredpowder is the hydrochioride oi the benzene sulfonic acid ester of2-methyl-4-amino-5-hydroxymethyl-pyrimidine.

The B-chioromethyl compound is obtained as iollows:

21.1 g. of 2-methyl--i-amino-5-aminomethylpyrimidine hydrochloridearesuspended in a finely puiverised form in 300 cos. of concentratedhydrochloric acid and treated with a concentrated aqueous solution of 7g. of sodium nitrite at 40-50 C., The mixture is heated to 40-50 C.

- until the evolution of'nitrogen is complete, poured into ice water,ether is poured over and the aqueous liquid rendered alkaline withpotassium car.-

bonate solution while stirring and'well cooling. Aiter repeatedextraction with ether and evaporation of, the solvent the2-methyl-4-amino-5- chloromethyl-pyrimidine remains in the form of 00'colorless crystals which melt at 163 C.

a The same compound may also be obtained in the following manner:

5 g; of z-methyl-4-amino-5 hydroxymethylpyrimidine are intimatelytriturated under 50 cos oi'chloroiorm with 8 g. of phosphorus pentachloride. The mixture' is heated to boiling for 1 hour,

while stirring. Alter the chloroform and the phosphorus oxychloridei'ormed have evaporated the hydrochloride oi2-methy1-4-amino-5-chloromethyl-pyrimidine remains which is transformedinto the free base by means of cold potassium carbonate solution. I

Example 2 216 grams of formyl glutaric acid ester, boiling at .115 C.under 3 mm. pressure, copper salt melting at C., are condensed with'96grams of acetamidine hydrochloride in a solution of 23 grams or sodiumin 1 liter of absolute alcohol. The2-methyl-4-hydroxy-pyrimidine-5-propionic acid ethylester formed meltsat 111 C.

With phosphorus oxychloride the 4-chl0rocompound boiling at ISO-131 C.under 4 mm. pressure is obtained in accordance with the method describedin Example 1. on heating to 120 C. with methylalcoholic ammonia in aclosed pressure'vessel a mixture is formed from which with dilutecaustic soda lye a by-product melting at 243 C. which has not beenexamined may be separated. The undissclved part is the 2-methyl-4-amino-pyrimidyl-5-propionic acid amide melting, at-195-200" C.,Therei'rom by Hoflmann's decomposition (compare the reaction conditionsin Example 1) the 2-methyl-4-amino-5-( s-aminoethyl) -pyrimidine isobtained. The hydrochloric acid salt melts at 64 C., its picrate at 229C.

Example 3 23 grams oi sodium are dissolved in 2 liters of absolutealcohol and boiled together with 202 grams of iormyl-succinic acid esterand grams of the hydrochloride of phenylacetamldine for 6 hours. Altercooling in ice water the crystals are filtered with suction anddissolved in caustic-soda solution. From this solution white crystalsmelting at 175' C. are .obtained. The

I Product is the 2-benzyl-4-hydroxy-pyrimldine-5 due decomposed with icewater. The aqueous solution is neutralized with sodium acetate and threetimes extracted with ether. The ethereal solution is extracted withcaustic soda solution .until the reaction is rendered alkaline, washedwith water and dried over sodium sulfate. After the ether has evaporatedan oil remains which boils unders mm. pressure at 188 C. It is the2-benzyl-4-chloropyrimidlne-5-acetic ester.

50 grams of the said substance are heated with 500 cos. of saturatedmethyl alcoholic ammonia for hours in an autoclave to 100 C. Aftercooling the crystals separating are filtered with suction andrecrystallized from alcohol. In this manner the2-benzyl-4-amlnopyrlmidine-5-acetamide is obtained in white crystalswhich melt at 239 C. v v

24.2 grams or the said substance are dissolved in a stirring apparatusin 5 liters of water while hot and the solution cooled to 5 C. Withinone hour a solution of 16 grams of bromine in 224 ccs.

of potassium hydroxide solution is added drop by drop and the mixturekept for 4 hours at this temperature. It is then heated for one hour onthe boiling water bath. After cooling to 20 C. the mixture is stirredwith 20 grams of benzaldehyde and 50 cos. of ether for 5 hours.Thereupon crystals separate which are filtered with suction and washedwith ether. The benzaldehyde compound is suspended in normalhydrochloric acid and distilled with steam until all benzaldehyde hasdistilled over. The aqueous clear solution is evaporated to drynessunder reduced pressure and the crystalline residue dissolved in alcoholand precipitated'with ether. In this manner crystals of the hydrochloricacid salt of 2-benzy1-4-amin0-. pyrimidyl-E-methylamine melting at 261C. with decomposition are obtained.

Example 4 31 grams of z phenyli-amino-5-amino-methyl-'pyrimidine-dihydrochloride are dissolved in 60 cos. of water and heatedto 50-60 C. while stirring. Within one hour a solution of 8 grams ofsodium nitrite in 100 ccs..of water is added drop by drop and thecontent of the vessel kept boiling at 132 C. under 2 mm. pressure areobfor further 2 hours at C. Then'the turbid solution is renderedalkaline with sodium carbonate and extracted with methylene chloride.The combined methylene extracts are extracted with dilute hydrochloricacid and the hydrochloric acid solution neutralized with sodium acetate.It is extracted with methylene chloride several times. After themethylene chloride has evaporated an oil remains which graduallysolidiiles to crystals. It is the 2-phenyl-4-amino-S-hydroxymethylpyrimidine the hydrochloric acid saltflof which melts at199 C. and the picrate of T which melts at 177 C. a

10 ,grams of 2-phenyl-4-amino-5-hydroxymethylpyrimidine-picrate aredissolved in 300' cos. of;glacial acetic acid and dry hydrogenbromideisintroduced into the solution at 35 C. until it is saturated.The solution is left standing for 18' hours and treated with ether untilcrystallization-commences. The crystals are filtered with suction andwashed with ether. the 2-;phenyl 4 amino-fi-bromomethylpyrimi-Inthismanner ass-macs l dine bromohydrate melting at 165' C. isobtained.

, Example 5 '11 grams of 2-methyl-4-chlorc-pyrimidyl-5- acetic ester areheated in an autoclave" for 10 hours to -130 C. with 650 cos. of 25%methyl alcoholic methylamine solution. The content is evaporated todryness and extracted with acetone while hot. 0n concentrating the2-m'ethyl-4- dine-bromohydrate melting at 165 C. is obtained. amide isobtained in crystals melting at 156- C.

By saponiflcationwith barlumhydroxlde the2-methyl-4-methylamino-pyrimidyl-5-acetic acid melting at 217 C. isobtained. Therefrom by boiling with alcoholic hydrochloric acid twocompounds, a solid one melting at 111 C., and an oil tained. Ontreatment with alcoholic ammonia from the two compounds the same2-methyl-4- methylamino-pyrlmidlne-fi-acetic acid amide is obtained. Thelatter yields according to the method specified above the2-methyl-4-methylamino-5-amino-methylpyrimidine boiling at C. under 3mm. pressure. The hydrochloric acid salt melts at 273 C.

When using in the above example instead of themethyl-alcoholicmethylamlne solution corwherein R stands iora substituent selected fromthe group consisting ofhydrogen and alkyl and R stands for alkyl,converting in the pyrimidine compound formed the hydroxyl group standingin the 4-position by the action of a phosphorus halide into halogen,replacing the latter by an amino group by the action or ammonia by whichsimultaneously the carboxylic acid estergroup in the substituent of the5-position of the pyrimidine nucleus is converted into the carboxylicacid amide group, transforming the latter according to Hoflmann'sdegradation reaction into the amino group and transforming thls'aminogroup into hydroxyl by the action of nitrous acid.

2. Process as claimed in claim 1, in.which the action of nitrous acid iseflected in the presence of excess concentrated hydrohalic acid.

3. The process which comprises reacting with a carboxylic acid amidineupon a compound of the formula:

amide group, transforming the latter according to Hoii'mann'sdegradation reaction into the amino group and transforming this aminogroup into. hydroxyl by the action 01' nitrous acid.

4. Process as claimed in claim 3, in which the action of nitrous acid iseflected in the presence of excess concentrated hydrohalic acid.

5. The process which comprisesreacting with acetamidine upon a compoundof the formula no-cn ta-uk i-cooni 7 0012 wherein it stands for asubstituent selected from the group consisting 01' hydrogen and alkyland R stands for alkyl, converting in the pyrimidine compound iormed thehydroxyl group standing in the 4-position by the action of a phosphorushalide into halogen. replacing the latter by an amino group by theaction of ammonia by which simultaneously the carboxylic acid estergroup in the substituent oi the 5-position oi the pyrimidine nucleus isconverted into the carboxylic acid amide group, transforming the latteraccording to Hoflmanns degradation reaction into the amino group andtransforming this amino group 25 into hydroxyl by the action or nitrousacid.

8. Processasclaimedinclaim 5.inwhichthe action of nitrous acid iseffected in the presence of excess concentrated hydrohalic acid.

'1. The process which comprises reacting with acetamidine upon acompound of the formula no-cn CHr-COOR wherein R stands for asubstituent selected from the group consisting of hydrogen and alkyl andR stands for alkyl, converting in the pyrimidine compound formed thehydroxyl group standing in the 4-position by the action or a phosphorushalide into halogen, replacing the latter by an amino group by theaction of ammonia by which caa'rrrrca'rs or common.

m Io. 2,377,395

June 5 191 HANS AFDRRSAG, ET AL.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction as i'ollals: Page 2,first column, line 12, for

man, 9, Example 5, strike out and insert 'tempraiaire' read--temperature-; page 5,

line 58, Example I, for "65.14." read .5";

btained." "dine-bromohydrate melting at C. is 0 insteadnethylamino-pyrimidylj-acetic acid methyland first colpage 1;, secondcolumn, line that the said Letters Patent should be read with thiscorrection therein that the same may conform to the record Signed andsealed this 2nd day of October,

(Seal) of the ease inthe Patent Office.

Leslie Frazer First Assistant Gamisaioner of Patents.

Hoii'mann's degradation reaction into the amino group and transformingthis amino group into. hydroxyl by the action 01' nitrous acid.

4. Process as claimed in claim 3, in which the action of nitrous acid iseflected in the presence of excess concentrated hydrohalic acid.

5. The process which comprisesreacting with acetamidine upon a compoundof the formula no-cn ta-uk i-cooni 7 0012 wherein it stands for asubstituent selected from the group consisting 01' hydrogen and alkyland R stands for alkyl, converting in the pyrimidine compound iormed thehydroxyl group standing in the 4-position by the action of a phosphorushalide into halogen. replacing the latter by an amino group by theaction of ammonia by which simultaneously the carboxylic acid estergroup in the substituent oi the 5-position oi the pyrimidine nucleus isconverted into the carboxylic acid amide group, transforming the latteraccording to Hoflmanns degradation reaction into the amino group andtransforming this amino group 25 into hydroxyl by the action or nitrousacid.

8. Processasclaimedinclaim 5.inwhichthe action of nitrous acid iseffected in the presence of excess concentrated hydrohalic acid.

'1. The process which comprises reacting with acetamidine upon acompound of the formula no-cn CHr-COOR wherein R stands for asubstituent selected from the group consisting of hydrogen and alkyl andR stands for alkyl, converting in the pyrimidine compound formed thehydroxyl group standing in the 4-position by the action or a phosphorushalide into halogen, replacing the latter by an amino group by theaction of ammonia by which caa'rrrrca'rs or common.

m Io. 2,377,395

June 5 191 HANS AFDRRSAG, ET AL.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction as i'ollals: Page 2,first column, line 12, for

man, 9, Example 5, strike out and insert 'tempraiaire' read--temperature-; page 5,

line 58, Example I, for "65.14." read .5";

btained." "dine-bromohydrate melting at C. is 0 insteadnethylamino-pyrimidylj-acetic acid methyland first colpage 1;, secondcolumn, line that the said Letters Patent should be read with thiscorrection therein that the same may conform to the record Signed andsealed this 2nd day of October,

(Seal) of the ease inthe Patent Office.

Leslie Frazer First Assistant Gamisaioner of Patents.

